5-arylindole derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein A, B, D, E, and F are each independently nitrogen or carbon; R 1  is hydrogen, C 1  to C 6  alkyl, --(CH 2 ) n  R 7 , or C 1  to C 3  alkyl-aryl; R 2 , R 3 , R 4 , R 5  and R 6  are each independently hydrogen, C 1  to C 6  alkyl, aryl, C 1  to C 3  alkyl-aryl, halogen, cyano, nitro, --(CH 2 ) m  NR 8  R 9 , --(CH 2 ) m  OR 9 , --SR 9 , --SO 2  NR 8  R 9 , --(CH 2 ) m  NR 8  SO 2  R 9 , --(CH 2 ) m  NR 8  CO 2  R 9 , --(CH 2 ) m  NR 8  COR 9 , --(CH 2 ) m  CONR 7  R 9 , or --(CH 2 ) m  CO 2  R 9  ; R 2  and R 3 , R 3  and R 4 , R 4  and R 5 , and R 5  and R 6  may be taken together to form a five- to seven-membered alkyl ring, a six-membered ary ring, a five- to seven-membered heteroalkyl ring, having 1 heteroatom of N, O, or S, or a five- to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S; R 7  is --OR 10 , --SR0 10 , --SO 2  NR 10  R 11 , --NR 10  SO 2  R 11 , --NR 10  CO 2  R 11 , --NR 10  COR 11 , --CONR 10  R 11 , or --CO 2  R 10  ; R 8 , R 9 , R 10  and R 11  are each independently hydrogen, C 1  to C 6  alkyl, or C 1  to C 3  alkyl-aryl; m is 0, 1, or 2; n is 2, 3, or 4; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are each independently phenyl or substituted phenyl, wherein said substituted phenyl may be substituted with one to three of C 1  to C 4  alkyl, halogen, hydroxy, cyano, carboxamido, nitro, or C 1  to C 4  alkoxy, and the pharmaceutically acceptable salts thereof. These compounds are useful in treating migraine and other disorders and are new. These compounds are useful psychotherapeutics and are potent serotonin (5-HT 1 ) agonists and may be used in the treatment of depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain, and chronic paroxysmal hemicrania and headache associated with vascular disorders, and other disorders arising from deficient serotonergic neurotransmission. The compounds can also be used as centrally acting antihypertensives and vasodilators.

This is a Divisional of application Ser. No. 08/600,931 now U.S. Pat.No. 5,849,739 which is the national stage application filed under 35U.S.C. 371 of PCT/IB94/00195 filed Jul. 4, 1994, which is a CIP of Ser.No. 08/115,282 filed Aug. 31, 1993 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to indole derivatives, to processes andintermediates for their preparation, to pharmaceutical compositionscontaining them and to their medicinal use. The active compounds of thepresent invention are useful in treating migraine and other disorders.

U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent ApplicationPublication Number 313397 refer to 5-substituted 3-aminoalkyl indoles.The compounds are said to be useful for the treatment of migraine.

British Patent Application 040279 refers to3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds aresaid to be useful in treating hypertension, Raymond's disease andmigraine.

European Patent Application Publication Number 303506 refers to3-poly:hydro-pyridyl-5-substituted-1H-indoles. The compounds are said tohave 5-HT, receptor agonist and vasoconstrictor activity and to beuseful in treating migraine.

European Patent Application Publication Number 354777 refers toN-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. Thecompounds are said to have 5-HT₁ receptor agonis: and vasoconstrictoractivity and to be useful in treating cephalic pain.

European Patent Application Publication Numbers 438230, 494774, and497512 refers to indole-substituted five-membered heteroaromaticcompounds. The compounds are said to have 5-HT₁ -like receptor agonistactivity and to be useful in the treatment of migraine and otherdisorders for which a selective agonist of these receptors is indicated.

European Patent Application Publication Number 313397 refers to5-heterocyclic indole derivatives. The compounds are said to haveexceptional properties for the treatment and prophylaxis of migraine,cluster headache, and headache associated with vascular disorders. Thesecompound are also said to have exceptional "5-HT₁ -like" receptoragonism.

International Patent Application PCT/GB91/00908 and International PatentApplication WO 91/18897 refers to 5-heterocyclic indole derivatives. Thecompounds are said to have exceptional properties for the treatment andprophylaxis of migraine, cluster headache, and headache associated withvascular disorders. These compound are also said to have exceptional"5-HT₁ -like" receptor agonism.

European Patent Application Publication Number 457701 refers to aryloxyamine derivatives as having high affinity for 5-HT_(1D) serotoninreceptors. These compounds are said to be useful for treating diseasesrelated to serotonin receptor dysfunction, for example, migraine.

European Patent Application Publication Number 497512 A2 refers to aclass of imidazole, triazole, and tetrazole derivatives which areselective agonists for 5-HT₁ -like receptors. These compounds are saidto be useful for treating migraine and associated disorders.

International patent application WO 9300086 describes a series oftetrahydrocarbazone derivatives as 5-HT₁ receptor agonists useful forthe treatment of migraine and related conditions.

Y. Yang, et. al describe the synthesis of 5-arylindoles in Heterocycles,Vol. 34, 1395 (1992) via palladium catalyzed cross-coupling reactions.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein A, B, D, E, and F are each independently nitrogen or carbon; R₁is hydrogen, C₁ to C₆ alkyl, --(CH₂)_(n) R₇, or C₁ to C₃ alkyl-aryl; R₂,R₃, R₄, R₅ and R₆ are each independently hydrogen, C₁ to C₆ alkyl, aryl,C₁ to C₃ alkyl-aryl, halogen (e.g. fluorine, chlorine, bromine oriodine), cyano, nitro, --(CH₂)_(m) NR₈ R₉, --(CH₂)_(m) OR₉,--SR₉, --SO₂NR₈ R₉, --(CH₂)_(m) NR₈ SO₂ R₉, --(CH₂)_(m) NR₈ CO₂ R₉, --(CH₂)_(m) NR₈COR₉, --(CH₂)_(m) CONR₇ R₉, or --(CH₂)_(m) CO₂ R₉ ; R₂ and R₃, R₃ andR₄, R₄ and R₅, and R₅ and R₆ may be taken together to form a five- toseven-membered alkyl ring, a six-membered aryl ring, a five- toseven-membered heteroalkyl ring, having 1 heteroatom of N, O, or S, or afive- to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O,or S; R₇ is OR₁₀, --SR₁₀, --SO₂ NR₁₀ R₁₁, --NR₁₀ SO₂ R₁₁, --NR₁₀ CO₂R₁₁, --NR₁₀ COR₁₁, --CONR₁₀ R₁₁, or --CO₂ R₁₀ ; R₈, R₉, R₁₀ and R₁₁ areindependently hydrogen, C₁ to C₆ alkyl, or C₁ to C₃ alkyl-aryl; m is 0,1, or 2; n is 2, 3, or 4; and the above aryl groups and the arylmoieties of the above alkyl-aryl groups are each independently phenyl orsubstituted phenyl, wherein said substituted phenyl may be substitutedwith one to three of C₁ to C₄ alkyl, halogen (e.g. fluorine, chlorinebromine or iodine), hydroxy, cyano, carboxamido, nitro, or C₁ to C₄alkoxy, and the pharmaceutically acceptable salts thereof. Thesecompounds are potent 5-HT₁ agonists with selectivity for the 5-HT_(1D)receptor and are useful in treating migraine and other disorders.

The compounds of the invention include all optical isomers of formula I(e.g. R and S stereogenicity at any chiral site) and their racemic,diastereomeric, or epimeric mixtures.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g. alkoxy), may be linear or branched, and they may also be cyclic(e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linearor branched and contain cyclic moieties.

Preferred compounds of the invention are compounds of the formula Iwherein B or E is nitrogen; A or F is carbon; R₁ is hydrogen, C₁ to C₃alkyl, or --(CH₂)₂ OCH₃.

The following compounds are particularly preferred:

3-(N-methylpyrrolidin-3-yl)-5-(pyrimid-5-yl)-1H-indole;

5-(pyrimid-5-yl)-3-(pyrrolidin-3-yl)-1H-indole;

3-[N-(2-methoxyethyl)pyrrolidin-3-yl]-5-(pyrimid-5-yl)-1H-indole;

3-(N-ethylpyrrolidin-3-yl)-5-(pyrimid-5-yl)-1H-indole;

5-(3-cyanopyrid-5-yl)-3-(N-methylpyrrolidin-3-yl)-1H-indole;

5-(3-cyanopyrid-5-yl)-3-(pyrrolidin-3-yl)-1H-indole;

5-(3-cyanopyrid-5-yl)-1H-3-[N-(2-methoxyethyl)pyrrolidin-3-yl]-indole;and

3-(N-methylpyrrolidin-3-yl)-5-(1,2,4-triazin-3-yl)-1H-indole.

The present invention also relates to a compound of the formula ##STR3##wherein X is halogen [chloride, bromide, iodide] or --OSO₂ CF₃ and R₁₂is hydrogen, methyl, or benzyl. These compounds are useful asintermediates in preparing compounds of formula I.

The present invention also relates to a pharmaceutical composition fortreating a condition selected from hypertension, depression, anxiety,eating disorders, obesity, drug abuse, cluster headache, migraine, pain,and chronic paroxysmal hemicrania and headache associated with vasculardisorders comprising an amount of a compound of the formula I or apharmaceutically acceptable salt thereof effective in treating suchcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating a conditionselected from hypertension, depression, anxiety, eating disorders,obesity, drug abuse, cluster headache, migraine, pain and chronicparoxysmal hemicrania and headache associated with vascular disorderscomprising administering to a mammal (e.g., a human) requiring suchtreatment an amount of a compound of the formula I or a pharmaceuticallyacceptable salt thereof effective in treating such condition.

The present invention also relates to a method for treating disordersarising from deficient serotonergic neurotransmission (e.g., depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, pain and chronic paroxysmal hemicrania and headache associatedwith vascular disorders) comprising administering to a mammal (e.g., ahuman) requiring such treatment an amount of a compound of the formula Ior a pharmaceutically acceptable salt thereof effective in treating suchcondition.

The present invention also relates to a method for treating disordersarising from deficient serotonergic neurotransmission (e.g., depression,anxiety, eating disorders, obesity, drug abuse, cluster headache,migraine, pain and chronic paroxysmal hemicrania and headache associatedwith vascular disorders) comprising administering to a mammal (eg., ahuman) requiring such treatment an amount of a compound of the formula Ior a pharmaceutically acceptable salt thereof effective in treating suchcondition.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I can be prepared via the following reactionscheme: ##STR4##

Compounds of formula III wherein X is halogen [chloride, bromide,iodide] or --OSO₂ CF₃ and R₁₂ is hydrogen, methyl, or benzyl can beprepared from the condensation of a compound of formula IV wherein X isas defined above with a compound of formula V wherein R₁₂ is as definedabove in an inert solvent. Suitable inert solvents include C₁ to C₃alcohols, acetic acid, formic acid, and N,N-dimethylformamide. Thepreferred solvent is acetic acid. The reaction is usually conducted at atemperature of from about 65° C. to about 154° C., preferably about 100°C. to about 110° C.

Compounds of formula II wherein X and R₁₂ are as defined above can beprepared via the reduction of a compound of formula III wherein R₁₂ isas defined above in an inert solvent. Suitable reducing agents includelithium aluminum hydride, lithium borohydride, and diborane. Lithiumaluminum hydride is the preferred reducing agent. Suitable inertsolvents include tetrahydrofuran, dioxane, diethyl ether, and otherethers. Tetrahydrofuran is the preferred solvent. The reaction isusually conducted at a temperature of from about 25° C. to about 100°C., preferably at about 65° C.

Compounds of formula VI wherein A, B, D, E, F, R₂, R₃, R₄, R₅, and R₆are as defined above can be prepared from a compound of formula VIIwherein A, B, D, E, F, R₂, R₃, R₄, R₅, and R₆ are as defined above, andZ is halogen [chloride, bromide, iodide] or --OSO₂ CF₃ via a transitionmetal catalyzed insertion reaction using hexamethyiditin in an inertsolvent, usually in the presence of a base, lithium chloride, andbutylated hydroxytoluene [i.e., 2,6-di-tert-butyl-4-methylphenol, BHT].Suitable catalysts are of palladium (II) and palladium (0) species, suchas palladium (II) acetate, palladium (II) chloride,bis(triphenylphosphine)palladium (II) chloride, andtetrakis(triphenylphoshine)palladium(0). The preferred catalyst istetrakis(triphenylphoshine)palladium(0). Suitable inert solvents includeethers, such as tetrahydrofuran and dioxane, acetonitrile,N,N-dimethylformamide, and N-methylpyrrolidin-2-one. Dioxane is thepreferred inert solvent. Suitable bases include tertiary amines, sodiumbicarbonate, and sodium carbonate. The preferred base is triethylamine.The reaction is usually conducted at a temperature between about 70° C.and about 210° C., preferably between about 90° C. and 154° C.

Compounds of formula Ia wherein A, B, D, E, F, R₂, R₃, R₄, R₅, R₆, andR₁₂, are as defined above can be prepared by the transition metalcatalyzed aryl cross-coupling reaction between a compound of formula IIwherein X and R₁₂ are as defined above and a compound of formula VIwherein A, B, D, E, F, R₂, R₃, R₄, R₅, and R₆ are as defined above in aninert solvent, usually in the presence of a base, lithium chloride, andbutylated hydroxytoluene [i.e., 2,6-di-tert-butyl-4-methylphenol, BHT].Suitable catalysts are palladium (II) and palladium (0) species, such aspalladium (II) acetate, palladium (II) chloride,bis(triphenylphosphine)palladium (II) chloride,tetrakis(triphenylphoshine)palladium(0). The preferred catalyst isbis(triphenylphosphine)palladium (II) chloride. Suitable inert solventsinclude acetonitrile, N,N-dimethylformamide, andN-methylpyrrolidin-2-one. N,N-dimethylformamide is the preferred inertsolvent. Suitable bases include tertiary amines, sodium bicarbonate, andsodium carbonate. The preferred base is triethylamine. The reaction isusually conducted at a temperature between about 70° C. and about 210°C., preferably between about 90° C. and 154° C.

Compounds of formula Ib wherein A, B, D, E, F, R₁, R₂, R₃, R₄, R₅, andR₆ are as defined above can be prepared from a compound of formula Iawherein R₁₂ is benzyl, and A, B, D, E, F, R₂, R₃, R₄, R₅, and R₆ are asdefined above via a reductive amination using an aldehyde of the formulaR₁₃ CHO, where R₁₃ is C₁ to C₅ alkyl, --(CH₂)_(s) R₇, or C₁ to C₂alkyl-aryl, s is 1, 2, or 3, and R₇ is as defined above, along with atransition metal catalyst, and a hydrogen source in an inert solvent.Suitable catalysts include palladium on carbon, Raney nickel, platinumoxide, and palladium hydroxide on carbon. The preferred catalyst ispalladium hydroxide on carbon. Suitable hydrogen sources includehydrogen gas, ammonium formate, and formic acid. Hydrogen gas at apressure of from about one to about three atmospheres is the preferredhydrogen source. Three atmospheres of hydrogen gas is the preferredpressure. Suitable solvents include C₁ to C₄ alcohols, acetonitrile,N,N-dimethylformamide, and N-methylpyrrolidine. Ethanol is the preferredsolvent. The reaction is usually conducted at a temperature of fromabout 25° C. to about 100° C., preferably about 25° C. to about 50° C.

Compounds of formula IV, formula V, and formula VII are eithercommercially available or can be prepared using methods known to oneskilled in the art. Aldehydes of the formula R₁₃ CHO wherein R₁₃ is asdefined above are also either commercially available or can be preparedusing methods known to one skilled in the art.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of from about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts various inorganic and organicacids. Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R₂ contains a carboxylate, are capable of forming base salts withvarious pharmacologically acceptable cations. Examples of such saltsinclude the alkali metal or alkaline-earth metal salts and particular,the sodium and potassium salts. These salts are all prepared byconventional techniques. The chemical bases which are used as reagentsto prepare the pharmaceutically acceptable base salts of this inventionare those which form non-toxic base salts with the herein describedacidic compounds of formula I. These non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium calcium and magnesium, etc. These salts can easily be preparedby treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction of maximum product of yields of the desiredfinal product.

The compounds of the formula I and the pharmaceutically acceptable saltsthereof (hereinafter, also referred to as the active compounds of theinvention) are useful psychotherapeutics and are potent serotonin(5-HT₁) agonists with selectivity for the 5-HT_(1D) receptor and may beused in the treatment of depression, anxiety, eating disorders, obesity,drug abuse, cluster headache, migraine, chronic paroxysmal hemicraniaand headache associated with vascular disorders, pain, and otherdisorders arising from deficient serotonergic neurotransmission. Thecompounds can also be used as centrally acting antihypertensives andvasodilators. The active compounds of the invention can be evaluated asanti-migraine agents by testing the extent to which they mimicsumatriptan in contracting the dog isolated saphenous vein strip [P. P.A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect canbe blocked by methiothepin, a known serotonin antagonist. Sumatriptan isknown to be useful in the treatment of migraine and produces a selectiveincrease in carotid vascular resistance in the anesthetized dog. It hasbeen suggested [W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989)]that this is the basis of its efficacy.

The active compounds of the present invention can also be evaluated viathe plasma protein extravasation response within the dura mater ofguinea pigs following unilateral electrical trigeminal ganglionstimulation, as described in Markowitz et al., J. Neurosci., 7 (12),4129-4136 (1987). The extent to which they mimic sumatriptan, in termsof both potency and efficacy, is determined in this assay.

The serotonin 5-HT₁ agonist activity is measured in in vitro receptorbinding assays as described for the 5-HT_(1A) receptor using rat cortexas the receptor source and [³ H]-8-OH-DPAT as the radioligand [D. Hoyeret al. Eur. J. Pharm., Vol. 118, 13 (1985)] and as described for the5-HT_(1D) receptor using bovine caudate as the receptor source and [³H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J.Neuroscience, Vol.7, 894 (1987)]. 5-HT agonist activity is defined byagents with affinities (IC₅₀ s) of 250 nM or less at either bindingassay.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, or example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycolate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., migraine) is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or "puff" of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

The following Examples illustrate the preparation of the compounds ofthe present invention and are not intended to limit in any way the scopeof the claims. Commercial reagents were utilized without furtherpurification. Melting points are uncorrected. NMR data are reported inparts per million (d) and are referenced to the deuterium lock signalfrom the sample solvent. Specific rotations were measured at roomtemperature using the sodium D line (589 nm). Unless otherwise stated,all mass spectrum were performed using electron impact (EI, 70 eV)conditions. Chromatography refers to column chromatography performedusing 32-63 μm silica gel and executed under nitrogen pressure (flashchromatography) conditions. Room temperature refers to 20-25° C.

EXAMPLE 1 3-(N-Methylpyrrolidin-3-yl)-5-(pyrimid-5-yl)-1H-indole

A mixture of 5-bromo-3-(N-methylpyrrolidin-3-yl)-1H-indole (0.450 g,1.86 mmol), 5-trimethylstannylpyrimidine (0.518 g, 1.86 mmol),bis(triphenylphosphine)palladium(II) chloride (0.100 g), triethylamine(0.84 mL, 6.03 mmol, 3.2 eq), lithium chloride (0.254 g), and2,6-di-tert-butyl-4-methylphenol (3.0 g) in anhydrousN,N-dimethylformamide (8 mL) was heated at reflux under nitrogen for 4hours. The resulting reaction mixture was evaporated under reducedpressure, and the residue was column chromatographed using silica gel(approximately 25 g) and elution with 9:1:0.1 [methylenechloride/methanol/ammonium hydroxide] afforded the title compound (0.089g, 0.32 mmol, 17%) as an off-white solid: mp, 140.0-143.0° C.; TLC R_(f)=0.20 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; ¹ HNMR (CD₃ OD)δ9.05 (s, 2H), 9.03 (s, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.47(d, J=8.4 Hz, 1H), 7.39 (dd, J=1.6 and 8.5 Hz, 1H), 7.16 (s, 1H), 4.90(s, 1 exchangeable H), 3.78-3.66 (m, 1H), 3.16 (t, J=8.7 Hz, 1H),2.92-2.84 (m, 1H), 2.72-2.59 (m, 2H), 2.42 (s, 3H), 2.42-2.33 (m, 1H),2.10-1.99 (m, 1H); ¹³ C NMR (CD₃ OD) d 156.6, 155.9, 138.9, 137.7,129.0, 125.4, 123.2, 121.4, 119.7, 118.7, 113.6, 63.5, 57.1, 42.6, 36.3,33.2; FAB LRMS (m/z, relative intensity) 279 ([MH]⁺, 100); HRMScalculated for C₁₇ H₁₈ N₄ 278.1533, found 278.1520.

EXAMPLE 2 5-(5-Cyanopyrid-3-yl)-3-(N-methylpyrrolidin-3-yl)-1H-indole

A mixture of 5-bromo-3-(N-methylpyrrolidin-3-yl)-1H-indole (0.500 g,1.79 mmol), 5-cyano-3-trimethylstannylpyridine (0.525 g, 1.97 mmol, 1.1eq), bis(triphenylphosphine)palladium(II) chloride (0.628 g, 0.90 mmol,0.5 eq), triethylamine (1.19 mL, 8.59 mmol, 4.8 eq, lithium chloride(0.235 g, 5.55 mmol, 3.1 eq), and 2,6-di-tert-butyl-4-methylphenol (40mg) in anhydrous acetontrile (5 mL) was heated at reflux under nitrogenfor 20 hours. The resulting reaction mixture was evaporated underreduced pressure, and the residue was column chromatographed usingsilica gel (approx 50 g) and elution with 9:1:0.1 [methylenechloride/methanol/ammonium hydroxide] to afford the title compound(0.060 g, 0.20 mmol, 11%) as a clear, pale brown oil: LRMS (m/z,relative intensity) 302 (M+, 29), 245 (8), 57 (100); HRMS calculated forC₁₉ H₁₈ N₄ 302.1528, found 302.1533.

EXAMPLE 3 5-Bromo-3-(N-methylpyrrolidin-3-yl)-1H-indole

To a stirred mixture of lithium aluminum hydride (1.10 g, 29.0 mmol, 2.2eq) in anhydrous tetrahydrofuran (60 mL) at 0° C. was added3-(5-bromoindol-3-yl)-N-methylsuccinimide (4.00 g, 13.02 mmol)portionwise cautiously. The resulting reaction mixture was heated atreflux under nitrogen for 2 hours. The reaction mixture was then cooled,and sodium sulfate decahydrate (approximately 20 g) was added slowly andcautiously, followed by the addition of water (approximately 2 mL) andethyl acetate (200 mL). The resulting mixture was stirred at roomtemperature under nitrogen for 2 hours, and then filtered throughCelite®. The filtrate was evaporated under reduced pressure to affordthe title compound (2.64 g, 9.46 mmol, 73%) as an off-white solid: mp,163.0-164.0° C.; TLC R_(f) =0.30 in 9:1:0.1 [methylenechloride/methanol/ammonium hydroxide]; ¹ H NMR (DMSO-d₆) δ11.0 (br m,NH), 7.74 (d, J=1.3 Hz, 1H), 7.29 (d, J=8.8 Hz,1H), 7.20 (br s,1H), 7.15(dd, J=1.7 and 8.6 Hz, 1H), 3.55-3.45 (m, 1H), 2.88 (t, J=8.2 Hz, 1H),2.62-2.42 (m, 3H), 2.29 (s, 3H), 2.28-2.21 (m, 1H), 1.90-1.80 (m, 1H);¹³ C NMR (DMSO-d₆) d 135.4, 128.2, 123.4, 122.9, 121.1, 118.3, 113.5,110.8, 62.6, 56.0, 42.1, 34.4, 32.2; HMRS calculated for C₁₃ H₁₅ BrN₂278.0415, found 278.0355.

EXAMPLE 4 3-(5-Bromoindol-3-yl)-N-methylsuccinimide

A solution of 5-bromoindole (4.00 g, 20.40 mmol) and N-methylmaleimide(5.00 g, 45.00 mmol, 2.2 eq) in glacial acetic acid (50 mL) was heatedat reflux under nitrogen for 120 hours. The resulting reaction mixturewas evaporated under reduced pressure, and the residue was stirredvigorously in a solution of ether/methylene chloride (9:1, 200 mL) for 2hours. Undissolved solid was filtered to afford the title compound (4.34g, 14.13 mmol, 69%) as a pale yellow solid: mp, 196.0-197.0° C.; TLCR_(f) =0.3 in diethyl ether; ¹ H NMR (CDCl₃) δ8.35 (br m, NH), 7.56 (d,J=1.5 Hz, 1H), 7.29 (dd, J=1.7 and 8.6 Hz, 1H0, 7.22 (d, J=8.7 Hz, 1H),7.08 (br s, 1H), 4.26 (dd, J=5.1 and 9.4 Hz, 1H), 3.28 (dd, J=9.4 and18.3 Hz, 1H), 3.11 (s, 3H), 2.87 (dd, J=5.1 and 18.3 Hz, 1H); FAB LRMS(m/z, relative intensity, NH₄ + as ionization source) 326 ([M(with ⁸¹Br)NH₄ ]⁺, 100), 324 ([M(with ⁷⁹ Br)NH₄ ]⁺, 96), 309 ([M(with ⁸¹ Br)H]⁺,21), 307 ([M(with ⁷⁹ Br)H]⁺, 20). Anal. calcd for C₁₃ H₁₁ BrN₂ O₂ : C,50.84; H, 3.61; N, 9.12. Found: C, 50.67; H, 3.43; N, 9.00.

EXAMPLE 5 5-Trimethylstannylpyrimidine

A mixture of 5-bromopyrimidine (4.00 g, 25.16 mmol), hexamethyiditin(9.06 g, 27.67 mmol, 1.1 eq), lithium chloride (1.27 g, 30.19 mmol, 1.2eq) tetrakis(triphenyl-phosphine) palladium(0) (1.13 g, 0.98 mmol, 0.04eq), and 2,6-di-tert-butyl-4-methylphenol (0.08 g) in anhydrous1,4-dioxane (45 mL) has heated at reflux under nitrogen for 16 hours.The resultant reaction mixture was evaporated under reduced pressure,and the residue was directly column chromatographed using silica gel(approximately 250 g) and elution with ethyl acetate/hexanes (1:1) toafford the title compound (4.75 g, 19.6 mmol, 78%) as a clear, paleyellow liquid: TLC R_(f) =0.6 in 1:1 ethyl acetate/hexanes; ¹ H NMR(CDCl₃) δ9.11 (s, 1H), 8.70 (s, 2H), 0.38 (s, 9H).

EXAMPLE 6 5-Cyano-3-trimethylstannylpyridine

A mixture of 3-bromo-5-cyanopyridine (0.58 g, 3.17 mmol) [C. Zwart andJ. P. Wibaut, Rec. trav. chim., 74, 1062 (1955)], lithium chloride(0.161 g, 3.80 mmol, 1.2 eq), 2,6-di-tert-butyl-4-methylphenol (12 mg),tetrakis(triphenylphosphine)palladium(0) (0.145 g, 0.13 mmol, 0.04 eq),and hexamethyiditin (1.14 g, 3.49 mmol, 1.1 eq) in anhydrous dioxane (6mL) was heated at reflux under nitrogen for 4.5 hours. The resultingreaction mixture was evaporated under reduced pressure, and the residuewas column chromatographed using silica gel (approx 50 g) and elutionwith 3:1 [hexanes/ether] to afford the title compound (0.68 g, 2.55mmol, 80%) as a white solid: mp, 77.0-79.0° C.; IR (KBr) 2231 cm⁻¹ ;R_(f) =0.4 in diethyl ether; ¹ H NMR (CDCl₃) δ8.79-8.77 (m, 2H), 8.01(dd, J=2.1 and 1.5 Hz, 1H), 0.38 (s, 9H); ¹³ C NMR (CDCl₃) δ158.4,151.7, 146.4, 138.3, 117.1, 110.3, 3.0.

I claim:
 1. A compound of the formula ##STR5## wherein A, B, D, E, and Fare each independently nitrogen or carbon, provided that three of A, B,D, E, and F are nitrogen; R₁ is hydrogen, C₁ to C₆ alkyl, --(CH₂)_(n)R₇, or C₁ to C₃ alkyl-aryl; R₂, R₃, R₄, R₅ and R₆ are each independentlyhydrogen, C₁ to C₆ alkyl, aryl, C₁ to C₃ alkyl-aryl, halogen, cyano,nitro, --(CH₂)_(m) NR₈ R₉, --(CH₂)_(m) OR₉, --SR₉, --SO₂ NR₈ R₉,--(CH₂)_(m) NR₈ SO₂ R₉, --(CH₂)_(m) NR₈ CO₂ R₉, --(CH₂)_(m) NR₈ COR₉,--(CH₂)_(m) CONR₇ R₉, or --(CH₂)_(m) CO₂ R₉ ; R₂ and R₃, R₃ and R₄, R₄and R₅, and R₅ and R₆ may be taken together to form a five- toseven-membered alkyl ring, a six-membered aryl ring, a five- toseven-membered heteroalkyl ring, having 1 heteroatom of N, O, or S, or afive- to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O,or S; R₇ is --OR₁₀, --SR₁₀, --SO₂ NR₁₀ R₁₁, --NR₁₀ SO₂ R₁₁, --NR₁₀ CO₂R₁₁, --NR₁₀ COR₁₁, --CONR₁₀ R₁₁, or --CO₂ R₁₀ ; R₈, R₉, R₁₀ and R₁₁ areeach independently hydrogen, C₁ to C₆ alkyl, or C₁ to C₃ alkyl-aryl; mis 0, 1, or 2; n is 2, 3, or 4; and the above aryl groups and the arylmoieties of the above alkyl-aryl groups are each independently phenyl orsubstituted phenyl, wherein said substituted phenyl may be substitutedwith one to three of C₁ to C₄ alkyl, halogen, hydroxy, cyano,carboxamido, nitro, or C₁ to C₄ alkoxy, with the proviso that when R₁ ishydrogen or C₁ to C₆ alkyl then R₂ and R₃, R₃ and R₄, R₄ and R₅, and R₅and R₆ must be taken together to form a five- to seven-membered alkylring, a six-membered ary ring, a five- to seven-membered heteroalkylring, having 1 heteroatom of N, O, or S, or a five- to six-memberedheteroaryl ring having 1 or 2 heteroatoms of N, O, or S, and thepharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein B or E is nitrogen; A or F is carbon; R₁ is hydrogen, C₁to C₃ alkyl, or --(CH₂)₂ OCH₃.
 3. A compound according to claim 1, whichis 3-(N-methylpyrrolidin-3-yl)-5-(1,2,4-triazin-3-yl)-1H-indole.
 4. Apharmaceutical composition for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprising anamount of a compound according to claim 1 effective in treating suchcondition and a pharmaceutically acceptable carrier.
 5. A pharmaceuticalcomposition for treating disorders arising from deficient serotonergicneurotransmission comprising an amount of a compound according to claim1 effective in treating such a disorder and a pharmaceuticallyacceptable carrier.
 6. A method for treating a condition selected fromhypertension, depression, anxiety, eating disorders, obesity, drugabuse, cluster headache, migraine, pain, and chronic paroxysmalhemicrania and headache associated with vascular disorders comprisingadministering to a mammal requiring such treatment an amount of acompound according to claim 1 effective in treating such condition.
 7. Amethod for treating disorders arising from deficient serotonergicneurotransmission comprising administering to a mammal requiring suchtreatment an amount of a compound according to claim 1 effective intreating such condition.